Prognostic importance of renal function in patients with early heart failure and mild left ventricular dysfunction

We evaluated the prognostic value of renal function in an initially “untreated” population with mild heart failure and compared the prognosis of this population with a matched controlled population. During a follow-up of 13 years (mean 11.7), 90 patients (56%) died. Mortality was higher compared with a matched controlled population. Multivariate Cox regression analysis demonstrated that beside the well-established risk markers of left ventricular ejection fraction and heart rate, renal function (estimated glomerular filtration rate, hazard ratio 1.16/10 ml/min/1.73 m2, p = 0.003) was the only additional independent predictor of cardiovascular mortality in patients with early heart failure. The aims of the present study were to evaluate whether renal function is an independent risk marker for cardiovascular mortality in patients with mild heart failure, and to establish the long-term prognosis of this population. Patients included in this analysis participated in the Dutch Ibopamine Multicenter Trial (DIMT), a multicenter heart failure study, as previously described.1 In summary, the study was a double-blind 6-month comparison of ibopamine, digoxin, and placebo in patients with mild heart failure (HF). Patients ranged in age from 18 to 75 years and were clinically stable for ≥2 weeks. Chronic heart failure was characterized by clinical signs and symptoms, and a radionuclide left ventricular (LV) ejection fraction <0.45 was obtained within the previous 2 months. Other inclusion and exclusion criteria were described in detail in the original publication.1 The population generally consisted of patients in New York Heart Association functional class II HF, and their mean LV ejection fraction was 0.29. Baseline data, including plasma neurohormones, were collected while these patients received only diuretics for their HF, because the clinical trials showing benefit of angiotensin-converting enzyme inhibitors and β-blockers in mild HF had not yet been published at that time (1988 to 1989). Estimated glomerular filtration rate (GFRc), using the Cockcroft-Gault equation ([140 − age in years] × [body weight in kg]/[72 × serum creatinine in milligrams per deciliter], in women multiplied by 0.85) was used as an indicator for renal function. Patient enrollment began in July 1989 and the last patient attended the last visit in October 1991. A total of 161 patients fulfilled all entry criteria. Follow-up was extended to a maximum of 13 years, which took place in 2002. Patients' physicians were contacted by telephone and were asked whether the patient was still alive. If the patient had died, cause of death was asked. Deaths were classified by their physicians, not centrally adjudicated, as cardiovascular death, sudden cardiac death, as defined previously,2 or noncardiac death. During follow-up, physicians were allowed to prescribe standard medication for HF, including angiotensin-converting enzyme inhibitors and β blockers. Data regarding use of medication were fully recovered until 1997. Statistics Netherlands provided data of the total mortality rate and cause of death of the Dutch population from 1990 to 2002. The data used from this control group were matched to age and gender with the DIMT population. We calculated person–years for each subject, commencing on the first day of inclusion and ending on the date of the last known vital status, emigration, or death. Expected numbers of deaths of the DIMT population were calculated on the basis of age- and gender-specific Dutch population mortality rates recorded by Statistics Netherlands. Data from 1990 to 2002 were applied. Data regarding the variables are presented as mean ± SD, unless indicated otherwise. For comparison of baseline data, Student's t test, Wilcoxon rank-sum-test (for non-normally distributed measures), and Fisher's exact test (for categorical measures) were used. To identify prognostic covariates that might have “explained” a difference in survival time, we estimated survival curves by the method described by Kaplan and Meier3 from the following variables: age, gender, LV ejection fraction, New York Heart Association functional class, heart rate, systolic blood pressure, GFRc, urea, hemoglobin, plasma norepinephrine, renin and aldosterone, use of diuretics, total exercise time, rhythm, HF etiology, and diabetes mellitus. Differences in survival times between groups were calculated using the log-rank test. All variables with a significance level of p <0.10 were introduced into a multivariate model as proposed by Cox.4 We checked the assumption of proportional hazards for each predictor variable by estimating the plots of the logarithm of the cumulative hazard. The end-multivariate model was constructed using a backward Wald analysis. The effect of ibopamine and digoxin on survival and other baseline characteristics that were prognostically relevant were also used in this analysis. Interaction terms were used to examine effect modification. For the statistical analysis, SPSS version 11.0 ( SPSS Inc., Chicago, Illinois) was used. Mean follow-up of our study population was 11.7 years (range 2.5 to 13.0). Follow-up was complete in 100% of the patients. At the end of follow-up, 90 patients (56%) had died. The major cause of death was cardiovascular (80%). Sudden cardiac death occurred in 51% of the deaths, progression of HF in 17%, stroke or rupture of abdominal aorta aneurysm occurred in 5%, and other cardiac causes in 7%. Of all noncardiovascular deaths (20%), (lung) cancer and pneumonia were the most common. Sudden cardiac death was equally high in both causes of HF (52% coronary artery disease vs 48% idiopathic dilated cardiomyopathy, p = NS). The baseline characteristics of the total population are listed in Table 1. The survivors were younger (p = 0.009), had a lower heart rate (p = 0.021), lower plasma norepinephrine levels (p = 0.043), and a higher LV ejection fraction (p = 0.005), GFRc (p = 0.021), and total exercise time (p = 0.015)